Researchers from more than 2 dozen large-scale epidemiological studies have reported a link between type 2 diabetes mellitus and cognitive impairment, cognitive decline, and dementia.1-5 Cognitive dysfunction is now considered by many researchers and clinicians to be an important late-life consequence of type 2 diabetes mellitus.5 Increasing attention has turned to whether clinical factors that predispose individuals to diabetes may confer increased risk of late-life cognitive dysfunction.

This article provides a focused discussion of 3 key diabetes-related risk factors that affect cognitive aging: obesity, insulin resistance, and the metabolic syndrome. Indeed, emerging data suggest that these conditions, which often precede the clinical diagnosis of diabetes, may be significantly associated with various forms of cognitive impairment, including Alzheimer disease (AD)—independent of diabetes or of the complications that often accompany that disease.

Obesity

The obesity epidemic is one of the most alarming public health concerns of our age—in large part because of its potential to lead to the development of diabetes.6,7 Given the rapid rise of obesity among young people, the late-life consequences of long-term obesity are garnering increased attention: recent findings indicate that midlife obesity and overweight may be associated with heightened risk of dementia, including AD, and vascular dementia.8

Results from the Cardiovascular Risk Factors, Aging, and Dementia study found that midlife obesity (body mass index [BMI] greater than 30 kg/m2) is related to dementia and AD.9 In a 21-year, follow-up, late-life cognitive assessment of 1449 individuals aged 65 to 79 years, researchers found significant 2-fold adjusted relative risk (RR) of dementia and AD. That risk was only mildly attenuated by further adjustment for midlife blood pressure, total cholesterol level, and smoking. In another long-term prospective study, Whitmer and colleagues10 found that midlife central obesity (as measured by sagittal abdominal diameter) was associated with a nearly 3-fold increased RR of dementia among 6583 adults 36 years later, even after adjusting for total BMI.

Notably, a dynamic relationship between obesity and cognitive aging has been described in which midlife obesity and increased adiposity appear related to risk of dementia, while late-life underweight and weight loss have also been found to be associated with increased dementia risk. Among 2798 adults in the Cardiovascular Health Study (mean age, 74.7 years) followed up for 5.4 years, the RR of dementia was significantly higher (RR, 1.4) among persons with midlife obesity (BMI, greater than 30) than among normal weight persons (BMI, 20 to 25). The pattern was reversed for late-life BMI: in late-life underweight persons (BMI, less than 20), the RR of dementia was significantly higher (RR, 1.6) than in normal weight persons.11

Evidence of this seeming paradox has been observed in other large-scale, long-term prospective studies.12 It appears that while midlife overweight and obesity are related to increased long-term risk of dementia, late-life underweight and weight loss may actually be early symptoms or markers of incipient dementia—rather than true short-term risk factors.

Insulin resistance

Obesity is a major risk factor for insulin resistance. Insulin resistance is typically accompanied by persistent elevations in blood insulin levels—a result of the reduced efficiency of cellular insulin uptake and utilization—and may have deleterious effects on cognitive aging. Insulin resistance is strongly associated with cerebral microvascular and macrovascular damage and may contribute to cognitive decline and vascular dementia. In addition, insulin resistance frequently accompanies elevations of inflammatory markers, such as C-reactive protein (CRP) and interleukin-6 (IL-6).13 Sustained increases in levels of inflammatory response compounds have been widely implicated in the development of vascular disease, but their involvement in the development of AD pathology has also been suggested.14

CHECKPOINTS

? Midlife obesity and overweight may be associated with heightened risk of dementia, including Alzheimer disease, and vascular dementia.

? Insulin resistance is strongly associated with cerebral microvascular and macrovascular damage and may contribute to cognitive decline and vascular dementia.

? Chronic inflammation, often indicated by the presence of high blood levels of inflammatory markers, may play a key role in the observed relationship between the metabolic syndrome and cognitive decline.

Furthermore, there may be cognitive aging effects of chronic hyperinsulinemia that are not mediated by vascular disease or injury. Insulin may directly affect levels of amyloid-β peptide (Aβ)—the primary component of neuritic plaques, a central element of AD pathology—which represents an alternative and intriguing pathway by which hyperinsulinemia may adversely affect brain health.15 Findings on the insulin-degrading enzyme provide a possible explanation for how hyperinsulinemia could lead to elevated levels of Aβ. Insulin-degrading enzyme is the major enzyme responsible for the breakdown of insulin in the body.16,17 It is also the first protease demonstrated to degrade Aβ; in laboratory studies, overexpression of insulin-degrading enzyme markedly reduced levels of both extracellular and intracellular Aβ.18-20 However, insulin-degrading enzyme binds more readily to insulin relative to other substrates, and insulin acts as a competitive inhibitor of Aβ degradation.16 Thus, the chronic hyperinsulinemia in insulin resistance may potentially interfere with Aβ clearance.21,22 Possible evidence for this in humans was provided in a report from Kulstad and colleagues.23 Patients with AD were found to have reduced insulin clearance and elevations in insulin-provoked plasma Aβ levels.

Nevertheless, an important distinction must be made between the effects of acute or temporary increases in insulin levels in the setting of normal metabolic function and those effects associated with insulin levels that are chronically elevated.21,24 An acute rise in insulin in response to glucose is a part of normal metabolism, but chronically high levels of blood insulin usually indicate insu-lin resistance. Finally, in addition to potential consequences of vascular damage and increased Aβ, Craft22 proposed that chronic peripheral hyperinsulinemia may actually induce a relative insulin-deprived state in the brain, which impairs normal glucose metabolism by neurons.